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Using a new and original in vivo imaging technique enabling real-time, in-depth, cellular immune response mechanism investigation in animals, researchers from the Institut Pasteur and Inserm have been the first to observe the process of graft rejection. Observing this "cellular choreography" has most notably proven the existence of a mechanism that contributes to the immune reaction underlying rejection. This discovery, published in Nature Medicine, paves the way towards the optimization of immunosuppressive therapies and promotes successful grafting techniques.
Graft rejection is the result of an attack on the graft by the host’s immune system. For grafts to succeed patients must receive immunosuppressive treatment that aims to reduce this defensive reaction against the graft, perceived as a foreign body. However, despite the progress in understanding in the field, the risk of rejection cannot be completely controlled and certain parts of the process remain unknown.
In an effort to clarify these mechanisms immunologists from the Institut Pasteur and Inserm - Philippe Bousso (1) and Susanna Celli (2), of the Dynamics of Immune Responses unit, and Matthew Albert (3), of the Dendritic Cell Immunobiology unit – have used high power microscopy technology to non-invasively film the cellular process in animals. It was on a murine ear skin graft model that they were, for the first time, able to watch in vivo, in real-time, and within the thickness of the tissues, the “ballet” of immune cells taking their places during the graft rejection.
Their observations revealed the existence of a hitherto unseen mechanism which has helped to explain the rejection. After reaching the graft following the alert signal called to launch the inflammatory response, certain immune system cells from the host are able to return to the lymph nodes presenting the killer cells, called lymphocytes, with a piece - or antigen – of the graft. Because of this continued flow, the army of lymphocytes set to target and destroy the graft is constantly being stimulated.
It was already known that graft cells could contribute to the host’s lymphocyte activation by presenting their own antigens. However, because they are rapidly destroyed by the immune system they alone didn’t seem capable of achieving graft rejection which, in some cases, takes place over a period of several months, or even years.
This study by Institut Pasteur and Inserm researchers reveals that the host's cells participate equally, and particularly efficiently, in the phenomenon by capturing donor antigens and transporting them directly to the killer cells. This work underlines the therapeutic importance of the development of anti-rejection treatments to block the back-and-forth flow of these cells.
(1) INSERM Research Director, head of Dynamics of Immune Responses unit (Institut Pasteur Inserm U668)
(2) Institut Pasteur senior scientist
(3) INSERM Research Director, Institut Pasteur laboratory head, head of Dendritic Cell Immunobiology unit (Institut Pasteur Inserm U818)
Visualizing the innate and adaptive immune responses underlying allograft rejection by two-photon microscopy, Nature Medicine, online on May 16, 2011.
Susanna Celli (1,2), Matthew Albert (3,4) and Philippe Bousso (1,2)
(1) Institut Pasteur, Dynamics of Immune Responses unit, 75015 Paris, France
(2) INSERM U668, Equipe Avenir, 75015 Paris, France
(3) Institut Pasteur, Dendritic Cell Immunobiology unit, 75015 Paris, France
(4) INSERM U818, 75015 Paris, France
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